Synthesis and evaluation of 7H-8,9-Dihydropyrano[2,3-c]imidazo[1,2-a]pyridines as potassium-competitive acid blockers

7H-8,9-Dihydropyrano[2,3-c]imidazo[1,2-a]pyridines with excellent physicochemical and pharmacological properties were identified that represent interesting candidates for further development as potassium-competitive acid blockers (P-CABs). The title compounds were prepared following synthetic pathways that relied either on a Claisen rearrangement/cross-metathesis reaction or on the (asymmetric) reduction of prochiral ketones. The influence of the character of the substituents R-3, R-6, and Ar on the biological activity and the physicochemical properties of the target compounds was examined. In contrast to the parent system (R-6 = H), compounds in which RI represents a carboxamide residue generally show improved in vivo activity and favorable pK(a)/log D values. Whereas variation of R3 is useful to obtain target compounds with modified basicity and lipophilicity, strong inhibition of the H+/K+-ATPase and potent in vivo activity is observed for RI = methyl only. Small modifications of the aryl group, e.g., replacement of hydrogen versus a fluoro atom or a methyl group, are allowed. The (9S)-enantiomers are responsible for the gastric acid secretion inhibiting action, whereas the (9R)-enantiomers are virtually inactive.